The purpose of the proposed research is to develop a multimodal approach to elucidate the combined effects of HIV infection and cannabis use on the brain in youth. An increasing proportion of new human immunodeficiency virus (HIV) infections occur in adolescents and young adults, or youth, living with HIV (YLWH; 25-30% in 2010). YLWH are in the midst of completing CNS development and will live with HIV infection and associated treatment for a long time. Evidence from adults suggests continuing CNS effects of HIV infection despite antiretroviral therapy; however, we know little about the impact of HIV infection and its treatments on the CNS in YLWH. Recent findings suggest significant cognitive impairments in behaviorally- infected YLWH, although the causal factors are unknown and likely multifactorial. Current theories of HIV- associated neuropathogenesis focus on the role of systemic and neural inflammation, although existing findings come largely from studies of adults with complex comorbidities and treatment histories. A better understanding of CNS changes in behaviorally-infected YLWH, then, will provide important insight and may have clinical implications regarding CNS pathogenesis. Of importance, this cohort is characterized by a high rate of cannabis use, which may impact the progression of HIV infection and associated cognitive and neurological alterations. Cannabinoids have been linked to greater immune suppression and increased vulnerability to infection; however, they also may alter cytokine and chemokine expression, driving an anti- inflammatory response. The literature suggests a potential increase in susceptibility to more rapid disease progression alongside parallel anti-inflammatory effects. Cannabis use in adolescence has been linked independently to changes in neuroimaging and cognitive functioning. The possibility of complex interplay among the CNS effects of HIV infection and cannabis use requires further investigation for guidance on the development of relevant treatment interventions in youth. The proposed study aims to explore the impact of cannabis use on HIV-associated CNS effects by studying YLWH (age 18-24) and control participants using an interdisciplinary approach that will include multimodal neuroimaging measures, plasma biomarkers of inflammation and immune function, and neurocognitive outcomes. This pilot project will initiate an essential characterization of the CNS effects of behaviorally-acquired HIV infection in YLWH; explore the impact of comorbid cannabis use; initiate the critical assessment of inflammation as a mediator of observed effects; and explore promising combinations of neuroimaging, plasma biomarker, and clinical variables for future studies. The resultant findings will set the stage for multisite, multi-disciplinary investigations by characterizing the neurologic and inflammatory signatures of HIV and comorbid cannabis use in youth and suggesting functionally meaningful biomarkers for identifying individuals at risk for CNS decline, monitoring effectiveness and toxicity associated with ART, and exploring interactions with other common substances of abuse.